Hexahydroisoquinoline and its derivatives are important synthetic intermediates to many morphinan compounds including burprenorphine, codeine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally, these compounds are analgesics, which are used extensively for pain relief in the field of medicine due to their action as opiate receptor agonists. However, nalmefene, naloxone and naltrexone are opiate receptor antagonists; they are used for reversal of narcotic/respiratory depression due to opiate receptor agonists.
Rice (U.S. Pat. No. 4,521,601) discloses the reduction of a dihydroisoquinoline to a tetrahydroisoquinoline by contacting the dihydroisoquinoline with sodium cyanoborohydride or sodium borohydride in refluxing 45% methanol for 1.5 hours. Rice further discloses Birch reduction of a tetrahydroisoquinoline to a hexahydroisoquinoline with lithium or sodium in liquid ammonia at −55° C. to −65° C. for 4 hours, then at −75° C. until none of the starting tetrahydroisoquinoline remains by thin layer chromatography. Because the borohydride reduction of a dihydroisoquinoline occurs in an achiral environment, the resulting tetrahydroisoquinoline must be resolved before further reaction. This resolution adds an extra step and reduces the yield of the desired enantiomer as half of the product has the undesired stereochemistry.
Uematsu et al. (J. Am. Chem. Soc. 1996, 113, 4916-4917) and Meuzelaar, et al. (Eur. J. Org. Chem. 1999, 2315-2321) disclose the asymmetric reduction of a dihydroisoquinoline with a chiral ruthenium catalyst in the presence of a 5:2 formic acid-triethylamine azeotropic mixture of salts in various aprotic solvents. These transformations typically have a reaction time of about 3 hours. Thus, more efficient processes having higher yields and enantiomeric excesses are desirable.